Acute Inflammation in Traumatic Brain Injury and Polytrauma Patients Using Network Analysis

Rowland, Bradley; Savarraj, Jude P.J.; Karri, Jay; Zhang, Xu; Cardenas, Jessica C.; Choi, H. Alex; Holcomb, John B.; Wade, Charles E.

doi:10.1097/shk.0000000000001349

Cited by 30 publications

(14 citation statements)

References 48 publications

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“…Thus, we assayed CCL2 in this study. TBI and intracerebral hemorrhage patients show elevated plasma and serum levels of CCl2 as early as 2 h onwards and show poor outcomes [59,60]. Our present study has shown increased CCL2 levels in the brain and the serum of weight drop-induced TBI mice.…”

Section: Mediators Of Inflammationsupporting

confidence: 59%

Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury

Kempuraj

Ahmed

Selvakumar

et al. 2020

Mediators of Inflammation

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Traumatic brain injury (TBI) is one of the major health problems worldwide that causes death or permanent disability through primary and secondary damages in the brain. TBI causes primary brain damage and activates glial cells and immune and inflammatory cells, including mast cells in the brain associated with neuroinflammatory responses that cause secondary brain damage. Though the survival rate and the neurological deficiencies have shown significant improvement in many TBI patients with newer therapeutic options, the underlying pathophysiology of TBI-mediated neuroinflammation, neurodegeneration, and cognitive dysfunctions is understudied. In this study, we analyzed mast cells and neuroinflammation in weight drop-induced TBI. We analyzed mast cell activation by toluidine blue staining, serum chemokine C-C motif ligand 2 (CCL2) level by enzyme-linked immunosorbent assay (ELISA), and proteinase-activated receptor-2 (PAR-2), a mast cell and inflammation-associated protein, vascular endothelial growth factor receptor 2 (VEGFR2), and blood-brain barrier tight junction-associated claudin 5 and Zonula occludens-1 (ZO-1) protein expression in the brains of TBI mice. Mast cell activation and its numbers increased in the brains of 24 h and 72 h TBI when compared with sham control brains without TBI. Mouse brains after TBI show increased CCL2, PAR-2, and VEGFR2 expression and derangement of claudin 5 and ZO-1 expression as compared with sham control brains. TBI can cause mast cell activation, neuroinflammation, and derangement of tight junction proteins associated with increased BBB permeability. We suggest that inhibition of mast cell activation can suppress neuroimmune responses and glial cell activation-associated neuroinflammation and neurodegeneration in TBI.

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Section: Mediators Of Inflammationsupporting

confidence: 59%

Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury

Kempuraj

Ahmed

Selvakumar

et al. 2020

Mediators of Inflammation

View full text Add to dashboard Cite

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“…IL-6, TNF and fractalkine were elevated in blood up to 6 months following injury [ 57 ]. TBI and polytrauma patients exhibit clinically relevant cytokine patterns in blood [ 58 – 60 ], CSF and brain-ECF [ 22 ], which was similar to what we noticed in our cohort, and demonstrates cytokine release from brain and other injured tissues.…”

Section: Discussionsupporting

confidence: 82%

Systemic inflammation alters the neuroinflammatory response: a prospective clinical trial in traumatic brain injury

Lassarén

Lindblad

Frostell

et al. 2021

J Neuroinflammation

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Background Neuroinflammation following traumatic brain injury (TBI) has been shown to be associated with secondary injury development; however, how systemic inflammatory mediators affect this is not fully understood. The aim of this study was to see how systemic inflammation affects markers of neuroinflammation, if this inflammatory response had a temporal correlation between compartments and how different compartments differ in cytokine composition. Methods TBI patients recruited to a previous randomised controlled trial studying the effects of the drug anakinra (Kineret®), a human recombinant interleukin-1 receptor antagonist (rhIL1ra), were used (n = 10 treatment arm, n = 10 control arm). Cytokine concentrations were measured in arterial and jugular venous samples twice a day, as well as in microdialysis-extracted brain extracellular fluid (ECF) following pooling every 6 h. C-reactive protein level (CRP), white blood cell count (WBC), temperature and confirmed systemic clinical infection were used as systemic markers of inflammation. Principal component analyses, linear mixed-effect models, cross-correlations and multiple factor analyses were used. Results Jugular and arterial blood held similar cytokine information content, but brain-ECF was markedly different. No clear arterial to jugular gradient could be seen. No substantial delayed temporal associations between blood and brain compartments were detected. The development of a systemic clinical infection resulted in a significant decrease of IL1-ra, G-CSF, PDGF-ABBB, MIP-1b and RANTES (p < 0.05, respectively) in brain-ECF, even if adjusting for injury severity and demographic factors, while an increase in several cytokines could be seen in arterial blood. Conclusions Systemic inflammation, and infection in particular, alters cytokine levels with different patterns seen in brain and in blood. Cerebral inflammatory monitoring provides independent information from arterial and jugular samples, which both demonstrate similar information content. These findings could present potential new treatment options in severe TBI patients, but novel prospective trials are warranted to confirm these associations. Graphical abstract

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“…IL-6, TNF and fractalkine were elevated in blood up to 6 months following injury [69]. TBI and polytrauma patients exhibit clinically relevant cytokine patterns in blood [70][71][72], CSF and brain-ECF [36], which was similar to what we noticed in our cohort, and speaks for a pronounced cytokine release from brain and other injured tissues. Altogether, we saw a relatively strong association between cytokines and age, sex as well as injury severity markers.…”

Section: Patient Demographics Affect Cytokine Levelssupporting

confidence: 87%

Systemic Inflammation Alters the Neuroinflammatory Response: A Prospective Clinical Trial in Traumatic Brain Injury.

Lassarén

Lindblad

Frostell

et al. 2021

Preprint

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Background: Neuroinflammation following traumatic brain injury (TBI) has been shown to be associated with secondary injury development, however how systemic inflammatory mediators affect this is not fully understood. The aim of this study was to see how systemic inflammation affects markers of neuroinflammation, if this inflammatory response had a temporal correlation between compartments and how different compartments differ in cytokine composition.Methods: TBI patients recruited to a previous randomized controlled trial studying the effects of the drug anakinra (Kineret®), a human recombinant interleukin-1 receptor antagonist (rhIL1ra), were used (n=10 treatment arm, n=10 control arm). Cytokine concentrations were measured in arterial and venous samples twice a day, as well as in microdialysis-extracted brain extracellular fluid (ECF) following pooling every 6 hours. C-reactive protein level (CRP), white blood cell count (WBC), temperature and confirmed systemic clinical infection were used as systemic markers of inflammation. Principal component analyses, linear mixed-effect models, cross-correlations and multiple factor analyses were used.Results: The development of a systemic clinical infection results in an altered brain-ECF cytokine response (e.g. increase in G-CSF and decrease in PDGF-ABBB, p<0.05 respectively), even if adjusting for injury severity and demographic factors. rhIL1ra administration had a strong effect on the inflammatory response, independently altering different blood (n=6) and brain cytokine (n=3) levels. No substantial delayed temporal association between blood and brain compartments could be detected. Jugular and arterial blood held similar cytokine information content, but brain-ECF was markedly different. No clear arterial to jugular gradient could be seen.Conclusions: Systemic inflammation, and infection in particular, alters cerebral cytokine levels, and rhIL1ra administration potently affects both systemic and cerebral cytokine levels. Cerebral inflammatory monitoring provides independent information from arterial and jugular samples, which both demonstrate similar information content. These findings could present potential new treatment options in severe TBI patients, and stresses the need of adequate monitoring of inflammatory markers.

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Acute Inflammation in Traumatic Brain Injury and Polytrauma Patients Using Network Analysis

Cited by 30 publications

References 48 publications

Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury

Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury

Systemic inflammation alters the neuroinflammatory response: a prospective clinical trial in traumatic brain injury

Systemic Inflammation Alters the Neuroinflammatory Response: A Prospective Clinical Trial in Traumatic Brain Injury.

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